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Fg7142 Attenuates Expression of Overexpectation In FG7142 ATTENUATES EXPRESSION OF OVEREXPECTATION IN PAVLOVIAN FEAR CONDITIONING Joshua Benjamin Bernard Garfield December 2008 This thesis has been submitted in fulfilment of the requirements for the degree of Doctor of Philosophy School of Psychology University of New South Wales Abstract The experiments reported in this thesis studied the mechanisms of expression of overexpectation of conditioned fear, as measured by freezing. In Stage I, rats were conditioned to fear a tone and a flashing light conditioned stimulus (CS) through pairings with a 0.5 mA, 1 s shock. In Stage II, overexpectation was trained by the reinforcement of a compound of these CSs with a shock of the same magnitude. Two compound – shock pairings produced an overexpectation effect, as measured by freezing to presentations of the tone alone, while further Stage II training caused over- training of overexpectation. Expression of the overexpectation effect produced by two compound – shock pairings could be prevented by pre-test injection of the benzodiazepine partial inverse agonist FG7142. This effect was dose-dependent and not due to state-dependent memory. Control experiments suggested that it was also not due to any general effect of FG7142 on the Pavlovian freezing response. Freezing to a tone that had been conditioned, but not subjected to any decremental training procedures, was unaffected by administration of FG7142 before either the conditioning or test session. FG7142 also did not affect freezing to a tone that had been subjected to an associative blocking procedure. The hypothesis that overexpectation of conditioned fear may be context-dependent was also tested. However, renewal was not observed. Rats that received Stage II training in a context distinct from the Stage I training context showed equivalent expression of overexpectation regardless of whether testing was conducted in the Stage I or Stage II training context. These results are consistent with the hypothesis that overexpectation, like extinction, leads to the imposition of a GABAA receptor-mediated mask on the fear CR. Moreover, they suggest that this masking of fear is the specific consequence of negative predictive error. i Table of Contents Abstract i Certificate of Originality vi Acknowledgements vii Manuscript and Conference Presentations ix Care and Use of Animals x List of Tables xi List of Figures xii Abbreviations xiv Introduction 1 Chapter 1. Behavioural characteristics of the learning and loss of fear 4 1. Acquisition of Pavlovian fear conditioning 5 1.1 The role of error-correction in the acquisition of conditioned fear 8 2. Extinction of Pavlovian fear conditioning 13 2.1 The contribution of error-correction to extinction 14 2.2 Reinstatement 17 2.3 Renewal 19 2.4 Spontaneous recovery 22 2.5 Theories of extinction 23 3. Overexpectation 31 4. Chapter 1 conclusion 44 ii Chapter 2. The neurobiology of the acquisition, expression, and loss of 47 conditioned fear 1. The role of the amygdala in the acquisition of conditioned fear 49 1.1. Theories regarding the role of the amygdala in storage of fear 53 memory 1.2. The neurochemistry of fear conditioning 55 2. The neuroanatomy of the expression of conditioned fear 65 3. Opioid receptor activation modulates detection of prediction error in 69 both acquisition and extinction of conditioned fear 4. The role of the amygdala in extinction 74 5. The prefrontal cortex in extinction 84 5.1. Plasticity of IL neural activity is associated with extinction 88 5.2. Role of NMDA receptors and intracellular signalling in mPFC in 90 extinction 6. Inhibition of amygdala neurons by IL activity as a possible substrate 92 for extinction 7. The role of the hippocampus in contextual modulation of extinction 94 8. Summary of models of extinction and conclusion 96 Chapter 3. Experimental reports 102 Experiment 1 102 Experiment 2 111 Experiment 3 118 Experiment 4 123 Experiment 5 131 Experiments 6a and 6b 135 iii Experiment 7 141 Experiments 8a and 8b 145 Experiment 9 150 Experiment 10 157 Chapter 4. General Discussion 162 1. Summary of empirical results and their theoretical implications 162 2. The over-training of overexpectation 166 3. Theoretical implications of the effect of FG7142 on expression of 172 overexpectation 3.1 A role for a comparator process? 173 3.2. How is fear masked after overexpectation? 175 4. What are the neuroanatomical substrates for the expression of 182 overexpectation? 5. The relationship between the pharmacology of FG7142 and the 184 disinhibition of fear 6. Conclusion 189 References 191 Appendix 1: Experiment 1 219 Appendix 2: Experiment 2 241 Appendix 3: Experiment 3 254 Appendix 4: Experiment 4 270 Appendix 5: Experiment 5 287 Appendix 6: Experiment 6a 294 Appendix 7: Experiment 6b 300 Appendix 8: Experiment 7 311 iv Appendix 9: Experiment 8a 321 Appendix 10: Experiment 8b 328 Appendix 11: Experiment 9 334 Appendix 12: Experiment 10 375 v Certificate of Originality ORIGINALITY STATEMENT ‘I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project's design and conception or in style, presentation and linguistic expression is acknowledged.’ Signed …………………………………………….............. Date …………………………………………….............. vi Acknowledgements First and foremost, I must acknowledge the indispensable contribution to this project, and my education in learning theory and neuroscience in general, by my supervisor, Dr. Gavan Patrick McNally. Thank you very much for your careful attention to my progress, my written work and presentations, and my experimental designs and results at every stage of my candidature. Thank you for your help, so many times, in charting the way forward, and your encouragement and reassurance when things didn’t seem to be going so well. It would be difficult, if not impossible, to understate your contribution to all that I have learned about this field in the past four years, and for stimulating my interest in it. Of course, I would never have come anywhere near the stage of doing a PhD if it were not for the love and support of my parents, Jay Lazar Garfield and Blaine Garson. Dad, since I was a toddler, you have actively stimulated my interest in science. Everything you have done, from teaching me about the different varieties of moss in the forest in Belchertown, to explaining the different types of infinities, to buying me books on astronomy, has contributed to the realisation of this thesis. Mom, your wisdom, encouragement, and belief in me were indispensable to getting me here. Thanks also to my brother, Abra James Coffin Garfield for the varied ways he supported me while I’ve lived in Sydney. Thanks for your supportive interest in my topic of study, which has helped maintain my own interest in it and shown me novel ways to think about it. And thank you most of all for getting me back into Ultimate, without which my experience of Sydney would have been considerably less colourful. vii To my partner, Troy-John William Emery, thank you for your love and support through all the trials and tribulations that have been part of my PhD studies. You endured 1 ½ years of a long-distance relationship, plus all my varied moods and eccentricities for much longer, and I’m so glad I can now share this ‘victory’ with you. Your affection and sense of humour are a haven for me amidst all the challenges I’ve faced. Thanks also to my comrades for their understanding and support. Your efforts inspire me with the hope that we can create a world where science will function to benefit all of humanity, rather than being distorted around the profit-motives of the corporate elite. Finally, thanks to all my office- and lab-mates, and various denizens of Level 6 for the innumerable ways in which they have helped, supported, and taught me. I could probably thank nearly every person who’s been involved in the McNally, Richardson, and Westbrook labs in the past 4 years, along with the rat attendants who have worked here in that time, and others in the School of Psychology as well. However, I’d particularly like to thank Melissa Wood, Kate Blatchford, Laura Bradfield, Sindy Cole, Julia Langton, Glynis Bailey, Lucy Choi, Marianne Weber, Adam Hamlin, Kelly Clemens, Christina Perry, Genevrie Hart, Jee Hyun Kim, and, finally, my co-supervisor Fred Westbrook. Thanks also to Justin Harris for his useful suggestions regarding possible interpretations of some of the data presented in this thesis. viii Manuscript Garfield, J. B. B. & McNally, G. P. (In Press). The effects of FG7142 on overexpectation of Pavlovian fear conditioning. Behavioral Neuroscience. Conference Presentations Garfield, J. B. B., & McNally, G. P. (2007). The role of GABAA receptor function in the expression of over-expectation. International Brain Research Organization World Congress of Neuroscience, Melbourne. Garfield, J. B. B. & McNally, G. P. (2007). FG-7142 prevents expression of over- expectation in Pavlovian fear conditioning. Neuroscience 2007, San Diego. Garfield, J. B. B. & McNally, G. P. (2008). FG7142, a benzodiazepine receptor partial inverse agonist, prevents expression of over-expectation in Pavlovian fear conditioning. 28th Annual Meeting of the Australian Neuroscience Society, Hobart. ix Care and Use of Animals The experiments presented in this thesis conformed to the guidelines on the ethical use of animals maintained by the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes (7th Edition), and all procedures were approved by the Animal Care and Ethics Committee at the University of New South Wales.
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